Okay, great. Welcome, everyone. I'm Yigal Nachumovitz. I'm one of the biotech analysts here at Citi. Welcome to the panel on Autologous Allogeneic CAR T, CAR NK, and more, exploring the state of play in cell therapy. It's my great pleasure to have with me today from Atara Biotherapeutics, Pascal Touchon, who's the President and CEO. From Caribou Biosciences, that recently went public, Rachel Haurwitz, President and CEO. From Cellectis, André Choulika, the CEO. From Gracell Biotechnologies, William Cao, the Chairman and CEO. Welcome all of you today. Thank you very much for taking the time.
I think as a starting point for those less familiar with each of your companies, maybe we could just go through and do a brief introduction to the company and the pipeline, and maybe comment as well on what you see as the strengths and differentiating qualities of your cell therapy platform. Maybe André, you want to kick it off?
Sure. Well, hello. Thank you very much for the nice introduction, Yigal, and it's appreciated. Cellectis is a gene editing company at the basis. We've been founded on the concept of gene editing at the start. We had the first wave of the gene-edited product that we started developing back a few years ago, I would say almost eight years ago, on the concept of using gene editing to make allogeneic CAR Ts. Since then, Cellectis has been developing series of product as allogeneic CAR T. We started with the first product that was the CD19 that licensed out to Servier that is currently shared between Servier actually, when we started with Servier, it was with Pascal. Pascal was with Servier at this time.
It was a very exciting time, and they licensed their U.S. rights to Allogene, so it's developed currently under the name of ALLO-501 or ALLO-501A. Then we have developed series of other CAR T in this space. Recently, we've announced also the launch of a new platform that is a gene editing platform for hematopoietic stem cells, and we're tackling the first type of disease that will be sickle cell disease, but there are a series of other type of diseases ranging from lysosomal storage diseases to immunodeficiencies. We have, since the summer, a full manufacturing ranging from buffers to DNA, RNA vectors and cell therapies that are manufactured internally. That's a quite quick overview of Cellectis.
Thank you very much, André. Rachel, tell us about Caribou in one minute.
Sure. Thank you, Yigal, for the invitation. Caribou is a CRISPR genome editing company. We were spun out of Jennifer Doudna's lab at UC Berkeley about nine years ago. During this time, we've actually invented our own proprietary next generation CRISPR technology. We call it the chRDNA platform, it has far more specific genome editing than first generation CRISPR-Cas9. We use this technology today with a focus on oncology. We're advancing two kinds of therapies in parallel. We're developing allogeneic CAR Ts for hematologic malignancies and allogeneic CAR NKs for solid tumors. The key theme that runs across all the work that we do is persistence. We believe that enhancing persistence is key to unlocking the broader opportunities for allogeneic cell therapies, I'd be happy to dive into more of those details as the conversation progresses today.
Perfect. Hi, William.
Hi. Gracell is founded in China, we have been developing two platforms technology trying to resolve the industrial bottlenecks. One is for autologous CAR. It takes weeks, and that's sort of industrial norm, and obviously that create not just cost, high cost, but also the time to deliver is an issue. Some of the patients could not wait or some of the patient, their disease progress to the next stage. We developed this FasTCAR, which is next-day manufacture, that way to resolve some of these issues. The TruU CAR, it's a standalone UCAR T. It's gene-edited, but we don't use anything else to suppress the allo reactions. Instead, we apply the dual CAR. One goes to kill the target cell and the other one to prevent rejection, sort of dual CAR approach.
We have a multiple pipelines in clinical trial, IIT trial, IND trials, and so late stage of early developments. We also have enhanced CAR for solid tumor, and that is based on gene editing. We have published the first IIT studies, that is a PD-1 knockout, whether it's TCR plus PD-1 knockout. It's autologous CAR for mesothelin-positive CAR T, and the result is encouraging in the sense of potential of autoimmune disease, and that's the most worrisome potential side effects. It turn out we didn't see any severe side effects. It gave us sort of baseline about safety tolerability. Now we have a second generation sort of enhanced CAR and flipped negative signal around and targeting certain solid tumors and also adapting the claudin 18.2 as a new target. Yeah, now most of people are in China, but we are spreading to Southern California. Yeah.
Thank you. Pascal?
Atara Bio is located in California. Atara Bio is a leading allogeneic T-cell immunotherapy company with a fully differentiated allogeneic cell therapy platform relying on EBV for Epstein-Barr virus T-cells from healthy donors. We have now three programs in the clinic, including what is arguably the most advanced allogeneic cell therapy in phase III, tab- cel, the first-in-kind BTD in oncology, soon to be submitted for regulatory approval in the EU and the U.S. We have also in phase II, a potentially transformative therapy for multiple sclerosis, which is now in a randomized control trial and has the potential to be the first-ever therapy in progressive MS to reverse disability. We have a pipeline of allogeneic CAR T in liquid and solid tumors, the two most advanced in terms of allogeneic CAR T going to the clinic next year.
One targeting CD19 as a potential best-in-class for B-cell malignancies, the other one targeting mesothelin for a number of solid tumors.
Perfect. Thank you. Let's get into a little bit more of a specific discussion about cellular therapy. I'd like to get an understanding from the panel as to what you see as the key hurdles and challenges associated with allogeneic therapies, allogeneic cell therapies, that is, and how you're thinking about edits to your cell therapies to overcome these challenges. Curious, André, you want to start?
Sure. Well, there is always pros and cons in any type of approach. Of course, one of the strengths of autologous therapies is that the cells are not rejected, unlike the protein gives an immune response that will be rejected. The fact is that there is longer persistence due to the fact that it's autologous. This is a double-edged sword. It's good if you are working, for example, in B-cell malignancies, because you can live without B-cell, that's fine. Finally, it reduces the space of the use of these type of technologies, essentially for NHL or ALL, et cetera, which remains something that is of high value but very limited.
A lot of different targets you cannot live with the CAR remaining in the body for years and years, and the CAR targeting the target, and it has to be something that persists enough to cure all the tumor and has to go afterwards. For example, if you're targeting targets such as mesothelin, that would be familiar to Pascal, or if you're targeting a target such as CD123, which is expressed on myeloid progenitors, you cannot survive without myeloid progenitors. You have to hit the target and go. It makes more sense if you want to extend this type of technology to series of different type of tumor-associated antigens and applications to something that would be turned off at a time. That's why I strongly believe that there is a space for autologous therapies in general.
The more it will go, the more I think autologous therapy are going to be very powerful in hospitals. A real industrial product that will be commercialized or regulated, et cetera, makes it difficult to spread this through series of different type of indications and an industrial process at the end. It makes more sense to try to edit the cells, try to work on their fitness state, try to have them extended over a period of time, and potentially develop an application of redosing person with patients, such as a consolidation therapy, instead of thinking of what has happened in the beginning of, let's say, CTL019, which is today Kymriah.
The one shot people get out from the disease and walks away and everything's fine. This is not the way these type of therapies are going to evolve in the future. It's going to be more sophisticated than this, and I believe also it's going to be probably also the potential of combo therapies at the end.
Okay, thanks. Rachel, do you want to give us your perspectives on what attributes are important to consider in designing an allogeneic cell therapy?
Yeah, absolutely. I'll hit on a similar theme as André did. Of course, one of the key differences for allogeneic CAR Ts relative to autologous CAR Ts is that they are foreign, and they will be subject to this fairly rapid immune-mediated rejection. So we are really focused at Caribou on enhancing the persistence of these cells. To André's point, it's not about keeping them forever, but it's about keeping them long enough to have sufficient and appropriate antitumor activity. At Caribou, we think about persistence in multiple orthogonal ways. Our lead program, CD19, is in a phase I study now, and it's an allogeneic anti-CD19 CAR T.
To the best of our knowledge, it's the first allo CAR T into the clinic with a PD-1 knockout. Our reason for removing PD-1 using our genome-editing technology is to prevent premature T-cell exhaustion, to maintain these allo CAR Ts in a high anti-tumor activity state for a longer period of time. Of course, this is one approach for persistence. An orthogonal approach is to actually prevent that rapid rejection by the patient's immune system. That's the strategy we take with our second program, CB-011. It's an allogeneic anti-BCMA CAR T on track for an IND filing next year. For this program, we manipulate HLA class I presentation through multiple genome-edits. We actually remove all of the endogenous class I presentation by knocking out a gene called beta-2 microglobulin, or beta-2m.
Then additionally, we site-specifically insert a transgene that encodes a fusion of beta-2m with HLA-E. This ensures that our product candidate is decorated only with HLA-E, with an eye to preventing both the patient's T cells and importantly, their natural killer cells from rapidly clearing these therapies. These two strategies are, of course, distinct and orthogonal and could potentially be additive depending on the tumor target. We're today exploring the opportunity to actually combine both of these in a single product candidate in the future.
William?
We are developing both autologous and allogeneic. To be very frank, at this moment, we do see and enjoy both advantage of both platforms. It's not conclusive based on our clinical experience. We have 15 products going through clinical IIT trial to de-risk the innovative designs. What we see with each platform, there are clear need for each platform, autologous, for obvious reasons, right? Also for very clear reasons, and I agree with both of you, the convenience and the redosing as allogeneic, and especially for some patients, you just can't have enough T cell from these patients for autologous CAR T. Also the cost and the waiting period and everything that goes to support allogeneic. Again, as André Choulika pointed out, the persistence, and that is the whole industry.
This is the challenge, whether you want to be long persistence or you want to deal with potential issues, you're putting switch in and then deal with potential CMC. There's a lot of issues, I think the future definitely is allogeneic. The question is still there. How long you want to keep these as a persistence, especially moving to solid tumor site. I don't believe that with a few shots of allogeneic CAR T, you can clear up the tumor mess or you might facing tumor lysis syndrome at that kind of fast speed. We're testing like everybody else. We are moving a UCAR T for multiple myeloma in addition to autologous. We are testing both. See, find their fit indications in the situations, that's where we are.
Thank you. I don't know, Pascal, did you want to add anything to that?
I certainly agree with William Cao that allogeneic is the future as well as with André Choulika and Rachel Haurwitz, that persistence and the adapted persistence of what you want to have in terms of durability of response is a key aspect there. We're looking at that with very different technology based on clinical experience, because we've already treated more than 300 patients with our platform, and we've been proving that it is safe to use our platform in these patients. There is no safety issue with these EBVT cells coming from healthy donors. We also proven that the cells are persistent enough for durable response.
What we're doing in terms of additional gene edit is really to further stimulate what I call the functional persistence, which is the ability of these cells not only to persist, but to persist in a state of activation and memory that allows them to be functionally persistent for long. We do that not only leveraging EBV T cells from healthy donors, but also in adding a new costimulatory domain called 1XX that has been invented by Michel Sadelain, Memorial Sloan Kettering, as well as a PD-1 dominant negative receptor for solid tumors on these cells.
We have data there at the preclinical level on this PD-1 DNR, and soon we will present data in a few months at a clinical stage that shows that this is helping the cell not only to persist functionally, but also to resist the immunosuppressive environment in solid tumors. The final point I'd like to make is the important of robust scale-up and manufacturing. We've proven that already.
We are making now with a new technology, some of our product in stirred tank bioreactor, where depending on the dose we can make like with ATA188 or MS product, we know we can make up to 20,000 doses from one leukopak. We are so advanced being in phase III and phase II and close to submission from one of our product that we've been able to develop a very robust manufacturing process that is scaled at a sufficient size to be able to treat patients in a very simple way. Again, we have a very large clinical experience with more than 300 patients treated already.
Thank you. You all sort of touched on this theme already in terms of the interplay between autologous and allogeneic, and as you mentioned, William, allogeneic is the future. That being said, I'm just curious more specifically if any of you wanted to comment on whether there'll still be a role for autologous in certain scenarios clinically.
I can start there and saying, because I work on both, as you know, Yigal, I think certainly the autologous up to the approved product, non-allogeneic product is approved. Certainly they have a place today, and they are saving lives today in the CD19 and BCMA space there. What's happening is that we see academic teams exploring new target with autologous, and I think that's great that academic teams can do that. It's very easy for them to do so, and that's going to de-risk a number of targets for many aspect there. I don't see a future for autologous moving forward for CAR T.
There might be a future when you need a kind of oligoclonal TCR response there, where it might be today with our current technology, still a bit challenging to make a product made of very different type of TCRTs there. We will find a way to get to that point. That's certainly where they have a space today, is if you don't have a CAR T or one TCR only, but you want to have multiple TCR to address a particular tumors there.
I cannot agree more with Pascal, actually, on what you just said. Autologous CAR T today save lives every day with fantastic products such as Kymriah, Yescarta is great product. There is also two other product that came out, one from BMS, one from Johnson & Johnson and Legend, like a BCMA CAR T. It is saving lives, but is it sustainable over time to do it in a way it's done industrially is a complication. I also agree very much with Pascal on one point, it will remain the therapy, but I think at a time it will loop up and go back to the hospitals and academic centers where it was born, actually, allogeneic autologous CAR T were essentially developed by University of Pennsylvania, the NCI, MSK, like Sloan Kettering, et cetera.
It will probably go back again in hospitals when you have a single very specific type of treatment, and it will be slowly replaced completely by allogeneic. It's a kind of a wave, but this wave will disappear. It will remain, but it will remain as bone marrow transplant, as a business for hospitals such as MD Anderson. It's a huge business for them, but it's not a business for pharma companies or biotech company on the long run. It could be on the short run. Now, when you discuss with most of the physicians that do cell therapies, one of the things they will tell you on a regular basis, it's becoming a total nightmare for most of them to treat patient for autologous therapy. Apheresis center are totally saturated. The number of clinical trials ongoing are huge.
All over the U.S., all over the rest of the world, it's becoming a complexity in logistics and market access for these things is impossible. It's not sustainable if you want to expand this to more than what it is today, and you will have to find a replacement to try effectively to tackle cancer. This is not the way to go.
Very interesting. Rachel, did you want to add anything?
I think my co-panelists have hit the highlights.
Okay. Very good. All right, well, moving on then. I'm curious how each of you are thinking about the relative interplay between CAR NK versus the CAR T cell therapies. Where does CAR NK have an advantage over CAR T and vice versa? Are there settings where potentially you could use both in a combo strategy? Curious anyone's thoughts on that.
Yeah. I will be happy to dive into that one, Yigal.
Okay.
At Caribou, our mindset is twofold as we think about these, two different kinds of therapies. We focus on hematologic malignancies using allogeneic CAR Ts, and we focus on solid tumors using allogeneic CAR NK. Why? As we look at the CAR T field, and especially the autologous CAR Ts that we've just been discussing, they're obviously tremendous proof of concept in terms of the power of the immune system to have anticancer activity.
I think that emerging field has also demonstrated how challenging it is to harness T cells in particular to have sufficient and appropriate antitumor activity in the solid tumor setting, where hematologic malignancies are challenging, solid tumors are even more challenging as we think about the need for trafficking and targeting, penetrating the tumor, overcoming the immunosuppressive tumor microenvironment, and dealing with the underlying heterogeneity of solid tumors.
At Caribou, our perspective is that natural killer cells are a better start point than T cells to try to tackle that litany of challenges, and we see the natural killer cell as the start point and not the endpoint. We're actually able to use our genome editing to make a variety of different edits to try to tackle a number of these different issues, including introduction of a CAR for antigen specific targeting. In order to do all of this, we actually start with iPSCs.
At Caribou we take iPSCs, edit them in a variety of ways to tackle these challenges, and then differentiate them using proprietary protocols that we've developed into natural killer cells with antitumor activity. We believe that this will be a really exciting and compelling approach to address the solid tumor compartment, which is obviously a huge unmet need as we think about the role of cell therapies in cancer care today.
Thanks. Maybe I can bring a different view. I think that's what the panel is for, probably, is to have divergent views as well as sometime aligning among. What we believe at Atara is the T-cell are the key cells, even in solid tumors. The reason why on PD-1 and on PD-L1 are working is because they allow T-cell to do their work. I think there have been so much experience now with all these checkpoint inhibitors about allowing the T-cells to really do their work and combat the cancer cells, that we still believe that T-cells are the key for both solid and liquid tumors. The challenge we see with NK cells is that they are fully differentiated cells that are short-lived in vivo. They're not supposed to persist. T-cells are there, are the memory cells.
They are the one having, especially when you have a phenotype in your product that is more into the central memory cells, you have cells that are supposed to persist long to be able to fight infection, and you use that to make sure that they can persist long enough for addressing the tumor there. NK cells are not supposed to stay, and they are not supposed to persist there. That's why there is a lot of engineering techniques there. If you look at what has been one of the key study to support NK cells, which was the great study by Katy Rezvani at MD Anderson.
What people tend to forget is that in that paper, if you read the paper carefully, you understand that these cells that were used in patient and were targeting CD19 CAR were in fact HLA match, partially match, for most of the patient, nine out of 11. They were idiotypic mismatch, and idiotypic mismatch is important for NK cells to be fully potent there. They were not fully allogeneic from that point of view. Even though they were not adding that durable response that is being seen with CAR T. We strongly believe that NK cells are possibly interesting and might give some short-term impact, but not to address the importance of durable remission in solid and liquid tumors. Sorry, back to the first question.
Let me switch back a little bit to defend the autologous CAR a bit, since we are doing both. There's reasons. We do have strong conviction with the autologous CAR. You got to give any technology product life cycle sufficient time. If you look any new technologies come and it go. What you get from clinical, it's real. It's solid. What we've seen, autologous CAR especially, I'm not promoting FasTCAR, but autologous CAR does give you long persistence without concern of safety issue. What we've seen from our patients, the CAR T can persist a year and a half, and sometimes they can pop up again, maybe responding to antigens, maybe not. There is no off-target, there is no other concerns, this is the beauty. Now, the CRS neurotoxicity can be resolved in our this duoCAR for multiple myeloma.
No neurotoxicity. One injection. You think about it, one injection in five days, the issue is gone. All standard of care for CRS grade one to two, it's gone, patients are recovered. 95% of patients achieve CR for a long time. That's a miracle. We cannot cover it up with issues. Autologous does have issues. Right now, this is a proven platform. Again, like everybody else here, we embrace the allogeneic. What we see from the program of T-ALL, targeting T-cell leukemia cells. Our goal was try to one shot and hopefully last long without stem cell transplantation. That was the design for that study. It turned out only one patient last CR without any events more than 18 months, but only 1. The rest of patients, six months, eight months or three months, they relapsed.
Now, for T-ALL is such aggressive disease, this is remarkable because there is no other standard of care, effective care. This let us think that, well, the design, maybe the persistence, maybe we need to put a certain signal transductions, maybe make it more persistent and so on. There's a lot of work need to do. Our 2nd generation UCAR T for B-cell malignancy is hitting clinical trials. This is the hope. I would not hold that hope that much that this is going to resolve or achieve the same persistence as autologous CAR T. We have a few years to go to manipulate the molecules that are important for persistence without increase the side effects. I believe this is where we are.
Now, back to the NK. The attractiveness, I think it's really drive by the hope of safety. The NK is really safe. Regardless of cord blood with little mismatch or iPS derived. I'm really excited about the future of iPS, because you can manipulate so much at this master bank without affecting the cargo size, without affecting the gene transduction or CAR NK or anything that you want to add on at a later stage. That's the beauty. One batch, much bigger than UCART. Now, we can make 300 doses of UCART, that's not ideal, right? We should make more to make a more batch, less batch variation. iPS is attractive. The current data, at least leading programs by other companies, that you need actually combination therapy.
Either additional antibody or IL-2, and efficacy is kind of at a par at the current autologous CAR T therapies. It is not sexy yet. There's a hope you can redose, lymphodepletion is trick. How many times you want to do lymphodepletion? Can we live without antibody assistance? If this is the hope for solid tumor, what kind of antibody combination with NK would pull the trick? There are unanswered questions or a lot of work need to be done testing clinical. That's our view.
Okay. Thank you, William.
Just a little word about the NKs. Just to come back to what you just said, Yigal Nachumovitz.
Sure.
Like what William said, also, combo is definitely. The enemy here is definitely cancer. Anything good to try to tackle cancer is great. I agree with Pascal and also Rachel. I agree with everyone, because everyone has an angle. Finally, the answer is always about the ability to try to blow out the tumor itself. For example, if you want to go against a solid tumor, what is interesting in a T-cell, they're super expandable, so they can expand very powerfully. What Pascal said definitely makes sense. In the PD-1 checkpoints inhibitors are very active on T-cells. They're not active on NK. On the other side, you see that NK can be very good in cleaning out some part of the solid tumor.
Why the concepts are trying to exclude one over the other, et cetera, and not trying to include everything in a potential therapy. For example, we're developing a CAR that targets fibroblast activation protein and the cancer-associated fibroblast that makes this protection for the tumor. You blow it out with T cells. You can add in checkpoint inhibitors. It depends the way also you design your T cells. It could attract the patient T cells after, once the immune system goes back and can turn the hot culture into hot tumor and potentially have a very strong effect on most of the solid tumor that are responsible to these type of checkpoint inhibitors. Then finally, you can potentially have a CAR NK injection to clean up the situation afterwards.
As we have to keep a focus, not on the technology we're using, but really on how to try to eradicate the tumor cell of the patient as cleanly as possible. I think all these approaches are very comprehensive. Not they have to be doable, but that's the concept that we're developing. I think definitely NK are really interesting. The simple fact that it's more easy to differentiate them from iPS cells and their access, et cetera. You can do all the engineering you want to do before you can access this. Definitely, T cells are the gate to these solid tumors.
Thank you. Thank you very much, André. William, you brought up lymphodepletion, which was on my list of questions. I'm curious how each of you are approaching lymphodepletion question, what strategy or strategies you are using to do the lymphodepletion to improve engraftment. Curious if you could comment on that. Thank you.
I can get started.
Go ahead.
As we have done a lot of things. Lymphodepletion, of course, we have the standard, which is Cy/Flu from all autologous phase that had been very extensively developed. It doesn't work without it most of the time, because you have to create space for your cell to expand. Even if you have an autologous cell, if you don't do Cy/Flu before, the engraftment will not happen so well. We've done Cy/Flu, but obviously, we have a second protocol. We made a comparison in the protocol for UCART22 and UCART123, where we do Cy/Flu and Cy/Flu, and we add alemtuzumab, which is a monoclonal antibody that would maintain the immune system down for a long period of time for the T cell to expand.
We've seen with the UCART19 or CD19 results or BCMA results, that you can have long persistence using the aid of alemtuzumab. You can see the CAR even three months after injection. Pretty long duration, over six months to one year of complete remission post the use of alemtuzumab. Alemtuzumab brings a lot to the lymphodepletion regimen, and the way to dose this is currently prepared for the phase II and the expansion pivotal trials with our partners. On the other side, I have also a new approach that we've also presented at the last ASGCT, which is cell lymphodepleting CAR. So CS1, the target CS1 is present on all immune cells, NK, T, macrophages, whatever, B-cells, et cetera.
We do Cy/Flu first, but dialing up or down the Cy/Flu to have more cells in order to enhance the cells to start the expansion and the antitumor effect makes it extremely interesting. You can see over 100, 104, 105 days after the injection of your CAR T CS1, the cells persist for a long period of time. self-lymphodepleting CAR, even though it is not easy to wield, it is something that is conceptually very interesting. Finally, what would be interesting is for example, the approach that is being described by Rachel, that could also be developed very extensively, which is the knockout of beta-2 microglobulin, which could open an NK attack versus beta-2 microglobulin replaced by HLA-E, which could block also NK with HLA-E.
Here it's interesting to see if you would lymphodeplete or not, and that's something that should be done, and I guess that you will have to lymphodeplete. It's a very, very important part of the secret sauce behind the CAR T development in general.
We at Atara have a slightly different experience there because we have with that cell in particular, and with ATA188, but with that cell specifically on hundreds of patients, an experience of expansion and persistence without lymphodepletion. The patient are being treated with no pretreatment, five to 10 unit infusion, and that's it. Only a two hours monitoring. That experience shows that the product is still able to expand and persist despite the fact there is no lymphodepletion. Of course, these patients that we're treating, most of them are immunocompromised. That might explain what's happening in this patient there. It's also linked to the fact that we have this partial HLA matching for the product there, and to the patients that might also allow more persistence.
The other experience we had is coming from Memorial, who did this clinical proof of principle that using an allogeneic CD19 EBV CAR T, you then have sufficient persistence to have very long durability of remission. In the patient they treated, they had an 83% complete remission that was maintained for more than two years. There's been no loss of response over 26.9 months median follow-up there. That's really the two experience. In that case, they had some lymphodepletion with Cy/Flu, a typical one. What we think is that it depends very much on the status of the patient and how long you want them to persist. There are some of our product allogeneic T-cells where we don't need lymphodepletion, and some others where we need some level of lymphodepletion, certainly not too long and not too heavy.
Maybe I'll dive in here as well, maybe a viewpoint in between these two. For our product candidates, we believe lymphodepletion is critical. It's a message we've heard from our SAB, from KOLs time and time again. The perspective we hear from them is that if you don't sufficiently lymphodeplete for these kinds of allogeneic CAR Ts, it really doesn't matter what bells and whistles you put on the product candidate using your genome editing if you don't create that window of opportunity for sufficient engraftment. Our strategy is to use a Cy/Flu combo. However, it is a more significant, more stringent approach than others have used in the allogeneic setting, so it leads to a deeper lymphodepletion. It's a protocol that was developed about a decade ago at the NIH.
It's been used for autologous CAR Ts and for TILs. There's quite a lot of safety data collected on it. We believe it will be important and impactful in the allogeneic setting in order to create that window that we believe will be necessary for sufficient antitumor activity.
Thank you.
Our experience echoed the importance of a lymphodepletion. Also, we clearly see the correlation, the level of lymphodepletion versus expansion of UCAR Ts. It's clear. The more you do, and then it's definitely creating an environment to favor expansion of UCAR Ts. The cost may be potential infection, and it's a very clear clinical science there. The key questions, I think, whatever we do, I think the goal is we want to win over autologous CAR Ts with persistent durations and CRS side effects. I think that's the key, and we are working on it. I think what we're trying to do is how long we need, what is the potential downside for that persistence we may face, we may need to explain to regulatory bodies.
I think for him, I think in a few years, we'll have a more perfect solution for him also. For solid tumor, I think even for autologous, we need to break through these barriers that Rachel mentioned, infiltration, particularly in tumor microenvironment. How do we let the UCAR T in harmony with the tumor microenvironment? I think that's something we need to work on. We are working on that, and hopefully we have data in the 12 months.
Okay. Thank you very much. All of you have run or are running phase I studies with the cell therapies. I'm curious if you could talk about some of the pitfalls for running early stage phase I trials with cell therapies. What are some of the pitfalls that you would advise someone entering into the same development strategy? Any thoughts there in terms of what to avoid with the early stage clinical trial with the cell therapy?
Maybe one thing to highlight is I think site selection is key, right? As we think about actually deploying these kinds of therapies, as you and others have highlighted in the discussion today, the potential risk for CRS and other side effects, there are locations across the United States and now across the world who have deep expertise in using these kinds of cellular therapies and being able to quickly detect the kinds of side effects that can be well managed and well treated. Certainly our experience has been that it's very beneficial and helpful to work with sites who are deeply expert in these arenas.
I couldn't agree with Rachel any more. When we had doing this clinical IIT in China, the variation among hospitals is significant, especially the experience dealing with CRS. With same degree of CRS, hospital A could, who had more experience, who can deal with the CRS in a standard way, and then a hospital with less experience may escalate the therapy easily so that you easily rate grade three because if you use it, there's a pressure. That need to be, I think, experience of the doctors and the hospitals is the key to give you quality data phase I. I think a more challenge to us, it is our experience, is when you have a normal design, for example, a FasTCAR, the dose required to achieve similar efficacy is about 50 times lower or at least 10 times lower.
What we do in the beginning, trying to submit application through ethics committees, they are strongly against from we start from low dose, typical dose escalation. That is a challenge. They do not want to let patient miss the opportunity of the benefit of potential therapy. They want we start a middle dose. They don't want to start low dose. They think it's not beneficial to patients. That is our challenge. After first one patient, if they're convinced to see a decent proliferation and they would agree to escalate higher dose, or vice versa. Those are our challenges.
I think I fully agree with Rachel and William there. We have a different set of challenge because we are running a phase III study with allogeneic cell therapy. We're also running a placebo control phase II outside of oncology and neurology. That's also leading to very specific challenge and what you need, of course, safety, but you need also to be able to treat patient in outpatient clinic. Like in our multiple sclerosis trial, we're not treating patients only that are hospitalized. They're all in outpatient clinic. They come and go for their treatment, like for monoclonal antibody.
This is a new experience for many of these doctors, so we have to train them, but that's very important because we believe it is the future of allogeneic cell therapy, that this therapy will be used like monoclonal antibodies in the future, depending of course, on the type of patients. In some patients could be used in outpatient clinic with just the two hours monitoring due to the safety profile that we can achieve there. Moving to phase II and phase III is leading to the need to go beyond expert centers and to be able to have a safety profile that is remarkable enough to be able to be used in many sites across the world. We're running these studies across three continents, in the U.S., in Europe, and in Australia.
We've seen that with good training of these investigators, they are able to use cell therapy, even neurologists are able to use cell therapy in a very safe and efficient way. Of course, oncologists and hematologists are more used to that, but they really can treat patient in outpatient setting with allogeneic cell therapy.
Okay, great. We're running out of time, but I'll do a quick lightning round if you'll allow me. Just go around the horn here and ask some company specific questions, maybe starting with you, Pascal. Could you just help set expectations for the data for the allogeneic mesothelin CAR T, the ATA2271? I believe you're going to have data in the fourth quarter of this year. Can you just give a quick overview of what we should expect?
Yeah. This product, ATA2271, is targeting mesothelin, still the autologous version. The allogeneic goes to the clinic next year. It's going to be the first time ever in patients that somebody has used a PD-1 dominant negative receptor CAR T as well as 1XX as a costimulatory domain. Data will be about safety, some data on efficacy, that will be just the first two cohorts, that's rather limited. Very importantly, we'll have data on expansion and persistence of the cells. That will be important because of the PD-1 dominant negative receptor and 1XX as a costim domain.
Thanks. Rachel, you've just started recently the phase I ANTLER study in BNHL for your lead product, CB-010. Curious what you would see as the criteria that you need to see to achieve proof of concept in that phase I trial.
Yeah, great question. Much like Pascal, this is a first example of a program with a particular kind of modification for persistence. In this case, this is the first allogeneic CAR T, to the best of our knowledge, with a PD-1 knockout. Obviously, we'll be learning not only specifically about the impact of this program in the BNHL setting, but more generally, the impact of the PD-1 knockout and understanding in what other product candidates it might be important in the future. This is a phase I study, of course it's officially about safety and tolerability, but clearly the benefit of working in the cell therapy space is the opportunity to collect and ultimately disclose emerging efficacy data as well. Certainly excited to share the first cut of data from this ongoing study sometime next year.
Thanks. Andre, for you, obviously your pipeline has been heavily focused on hematologic malignancies, but I know you've said in the past solid tumors are part of your long-term plan. Could you talk a bit about transitioning the pipeline for your cell therapy to solid tumors and your strategy there? Thanks.
We have presented three programs that are going to go into clinic starting next year. It's probably going to stage them because it's going to be a lot. We have our first allogeneic mesothelin CAR T that we're pushing into the clinic somewhere in 2022. It has a specific interest in there, which is the knockout of TGF-beta R2 receptor to try to remove all the negative feedback loop that you can have in the solid tumor microenvironment. The knockout of TGF-beta R2 can provide some insights on the way the cells to behave for these type of solid tumors. It's a very exciting CAR. We have excellent results so far in pre-clinic, and it will be pushed forward.
The next CAR T, for solid tumor that we're pushing forward is this fibroblast activation protein to try to turn cold tumor into hot tumor that could be done potentially in clinical trial in combo, that could unleash a lot of different targets of tumors that do not respond to checkpoint inhibitors, in this case could potentially become checkpoint inhibitor potent. That could open the gate for a lot of different type of application in this array of different type of solid tumor where FAPs are really playing some key role.
Finally, the last but not least, which is a super interesting, very sophisticated that we're going to push in triple-negative breast cancer, which is MUC1, that have the three knockouts, two knock-ins, and the TGF-beta R2 dominant negative that will be expressed there. That's probably for later. It's still early stage. I think these three CARs are in the pipeline in terms of will be pushed into clinic starting next year.
Okay, great. Finally, quickly for William, just talk about the next day manufacturing, and does next day manufacturing, in your view, render the off-the-shelf therapies as potentially unnecessary, or will there still be a role for off-the-shelf therapies in a world where we have next day manufacturing?
First of all, the FasTCAR or the next day manufacture still require it is a person-to-person. The QC hits each person. It is unlike the UCAR T, 1 batch QC, that's it, right? There is a clear difference here. Of course, the FasTCAR is still autologous, and it really carries the advantage of the autologous CAR T. We are very excited to see the safety profile of a duoCAR, and it has so much to manipulate to make a safer but highly efficacious duoCARs. As our clinical data shows, our high dose now so far has been 11 patients, 100% sCR, and with a sound safety profile without any neurotoxicity. We decide to move into frontline therapy for high-risk population. That's a sort of game changer.
If that happens, we got a license to move on frontline, and we're very excited and hope we can present the data very soon because this is the representation of CAR T therapy in frontline, and that's exciting.
Thank you all, Pascal, André, Rachel, and William. Thank you all so much for a very lively discussion. We appreciate it very much. Good luck with the rest of the conference, and we'll be in touch.
Thank you.
Thank you. Thank you all for the opportunity. Thank you.
Bye.